Developmental and Reproductive Physiology of Small Mammals at High Altitude: Challenges and Evolutionary Innovations Cayleih E
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© 2020. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2020) 223, jeb215350. doi:10.1242/jeb.215350 REVIEW Developmental and reproductive physiology of small mammals at high altitude: challenges and evolutionary innovations Cayleih E. Robertson1,* and Kathryn Wilsterman2 ABSTRACT xanthopygus,Krameretal.,1999;Ochotona curzoniae,Cietal., High-altitude environments, characterized by low oxygen levels and 2009). For example, the animal with the highest known distribution in low ambient temperatures, have been repeatedly colonized by small the world is the yellow-rumped leaf-eared mouse (P. xanthopygus, ∼ altricial mammals. These species inhabit mountainous regions year- adult body mass 55 g), which was recently found to inhabit sites round, enduring chronic cold and hypoxia. The adaptations that allow >6700 m above sea level (Storz et al., 2020). small mammals to thrive at altitude have been well studied in non- Integrative studies of ecology, population genetics and reproducing adults; however, our knowledge of adaptations specific physiology have identified numerous adaptations that allow small to earlier life stages and reproductive females is extremely limited. In endotherms to thrive at HA despite significant and pervasive lowland natives, chronic hypoxia during gestation affects maternal physiological challenges (reviewed in McClelland and Scott, 2019). physiology and placental function, ultimately limiting fetal growth. With very few exceptions, studies on these small HA mammals have During post-natal development, hypoxia and cold further limit growth focused exclusively on the traits of non-reproducing adults (Ivy and both directly by acting on neonatal physiology and indirectly via Scott, 2015). In contrast to many HA-native bird species, small HA impacts on maternal milk production and care. Although lowland mammals inhabit mountainous regions year-round, meaning they natives can survive brief sojourns to even extreme high altitude as undergo their entire reproductive cycle under conditions of chronic adults, reproductive success in these environments is very low, and cold and hypoxia. Despite the fundamental importance of lowland young rarely survive to sexual maturity in chronic cold and reproductive success for fitness, the reproduction, growth and hypoxia. Here, we review the limits to maternal and offspring development of these HA-adapted species has been largely ignored. physiology – both pre-natal and post-natal – that highland-adapted For young mammals, who are small and physiologically immature, species have overcome, with a focus on recent studies on high- the cold and hypoxic HA environment poses unique energetic altitude populations of the North American deer mouse (Peromyscus and physiological challenges (both pre-natally and post-natally) maniculatus). We conclude that a combination of maternal and compared with those experienced by adults. As such, developing developmental adaptations were likely to have been critical steps in mammals may require unique physiological solutions to cope with the evolutionary history of high-altitude native mammals. their environment. In addition, the physiology of developing mammals is inextricably linked to that of their mother, who shapes KEY WORDS: Fetal growth, Gestational adaptations, High altitude, both the pre-natal and post-natal environment of her offspring (Wells, Maternal care, Post-natal development 2019; Wolf and Wade, 2009). The adaptive evolution of reproductive traits at altitude is therefore likely to be a function of both maternal Introduction: adaptation to high-altitude environments and offspring physiology, as well as the complex interactions between ‘One reason to focus on the physiology of juveniles and nestlings is the two (Fig. 1, arrows). In this Review, we discuss the energetic and that for most individuals it is the only physiology ever experienced’ physiological challenges posed by chronic hypoxia and cold to reproduction in small mammals, and we review what we know about Hill (1983). the physiological adaptations during gestation and early life that have The abiotic factors characteristic of high-altitude (HA) environments allowed some species to be highly successful at HA. pose significant energetic challenges to their inhabitants. Animals endemic to alpine regions must cope with chronic cold exposure – as Pre-natal challenges ambient temperature drops on average 2°C with every 300 m gain in We have known for nearly a century that altitude directly challenges elevation – alongside unremitting hypobaric hypoxia, which limits the very first steps in mammalian development. At altitude, fetal aerobic metabolism (Körner, 2007). This combination of stressors growth is reduced as much as 30% in lowland-native mammals, (hypoxia and cold) is particularly challenging for small endotherms including mice, rats, guinea-pigs, humans and sheep (Bailey et al., whose high surface area to volume ratios promote rapid heat loss. The 2019; Gilbert et al., 1979; Matheson et al., 2016; Parraguez metabolic demands of this environment routinely push these small HA et al., 2005, p. 200; Royer et al., 2000; Scheffen et al., 1990; Turan _ endotherms close to their V O2,max (see Glossary; Hayes, 1989). Yet, et al., 2017; Weihe, 1965). In addition, many lowland-native rodents despite these energetic challenges, small rodents and lagomorphs are experience increased rates of fetal death when gestating under the animals with the highest altitudinal distributions across numerous experimental hypobaric hypoxia (Gilbert et al., 1979; Kelley and mountain ranges (e.g. Peromyscus maniculatus, Hock, 1964; Phyllotis Pace, 1968; Matheson et al., 2016). Adaptation to altitude has ameliorated fetal growth restriction in the two mammals that have 1Department of Biology, McMaster University, Hamilton, ON, Canada L8S 4K1. been studied to date: highland-adapted human populations (including 2Division of Biological Sciences, University of Montana, Missoula, MT 59802, USA. native Andeans and Tibetans; Moore, 2017b) and multi-generational highland sheep (Parraguez et al., 2005). Although no one has yet *Author for correspondence ([email protected]) examined the degree to which altitude adaptation may protect fetal C.E.R., 0000-0002-6769-2852; K.W., 0000-0001-7262-9754 growth in any small mammal, the dramatic effects of altitude on fetal Journal of Experimental Biology 1 REVIEW Journal of Experimental Biology (2020) 223, jeb215350. doi:10.1242/jeb.215350 The physiological traits relevant to fetal growth are both maternal Glossary and fetal. Essentially all major maternal physiological systems are Implantation modified by pregnancy to facilitate the metabolic demands of fetal The process by which the blastocyst attaches to and, in some species, growth (for a detailed review, see Napso et al., 2018). In particular, embeds itself within, the uterine wall. Implantation is the first step in the respiratory, cardiovascular and hematological systems all placentation in which connections between maternal and fetal tissue are increase their capacity or otherwise modify their function in order established. It is essential to the further development of the embryo and successful gestation. to facilitate sufficient gas exchange and nutrient delivery to the feto- Tidal volume placental unit (Napso et al., 2018). Thus, the first major challenge to Volume of air taken into the lungs during a single breath. reproduction at altitude is ensuring that systemic changes to Trophoblast maternal physiology can fulfil delivery demands at altitude, where A class of cells that are derived from the outer layer of the blastocyst. the partial pressure of oxygen is lower than at low altitude. Once Trophoblasts differentiate from a general stem cell type into an array of oxygen (and nutrients) reach the site of implantation (see Glossary), specialized trophoblasts that perform specific functions, including facilitating implantation and building the placenta. their delivery and realized utility to the fetus depend on fetal V_ hematology – which is particularly important for oxygen uptake – O2, max Maximal whole-animal oxygen consumption, indicative of maximum and of course on the structure and function of the placenta, which _ capacity for aerobic metabolism. V O2, max can be elicited by exercise or gates nutrient transfer between mother and fetus. _ cold. The exercise and cold-induced VO2, max values for a given individual _ are not always the same. Cold-induced VO2, max (thermogenic capacity, _ Maternal physiology V O2, summit) is the product of both shivering and non-shivering thermogenesis. Chronic hypoxia at altitude may constrain fetal growth by inhibiting or altering gestational remodeling of maternal physiology, resulting in insufficient gas exchange and nutrient delivery to the implantation site. In humans, changes to maternal respiratory and death rates and growth in lowland species suggest that fetal growth cardiovascular function that occur in lowlanders at altitude are is a critical challenge that highland-resident small mammals must sufficient to match oxygen content in maternal circulation measured overcome. in highlanders (Moore et al., 2001; Zamudio et al., 2007b), In this part of the Review, we draw on literature exploring the suggesting that oxygen availability in maternal circulation is not the effects of gestational hypoxia on the site of placentation in critical challenge for fetal growth at altitude (Postigo et al., 2009; laboratory strains of lowland rodents, and